Peripheral B cells play a major role in initiating protective responses directed against a large number of pathogens. The transformation of activated and naive peripheral B cells accounts for approximately 90% of all human lymphomas. While numerous advances have been made in obtaining a molecular understanding of the development and survival of follicular and marginal zone B cells in mice, much less is understood about these populations in humans. Indeed major discrepancies exist between some of the conceptual views that are currently emerging about marginal zone B cells in mice as compared to generally held views regarding marginal zone B cells in humans. It appears likely that two distinct types of marginal zone B cell may exist in most vertebrates, a "naive" type of marginal zone B cell and a "memory" type of marginal zone B cell. Very little is understood about follicular precursors in humans of mature follicular and marginal zone B cells, and very little information exists regarding survival pathways involved in the maintenance of different human peripheral B cell populations. An understanding of these pathways in non-transformed peripheral B cells is critical in attempting to define pathways that are of pathogenetic significance in human lymphoid malignancies. Studies are proposed to delineate human splenic and lymph node derived follicular and marginal zone B cell populations and their presumed precursors using in part insights obtained from the study of murine peripheral B cells. Profiles of gene expression in these human B cell populations will be compared with proteomic approaches to identifying Akt and PKC substrates in these purified cell types. A chromatin immunoprecipitation approach will be used to identify molecular targets of NF-kappaB in distinct peripheral B cell populations. Specific function and survival oriented molecular profiles will thus be obtained of human marginal zone B cells and follicular B cells. Insights may thus be obtained that are relevant to understanding the role of specific human B cells in defense against pathogens, including blood borne pathogens relevant from a bioterrorism context, and a more detailed understanding of molecular parameters relevant to peripheral B cell survival, of relevance to lymphomagenesis, may ensue.